Benzodiazepines have been used for several decades, but have become increasingly popular because of their effects and their low toxicity compared to other drugs of similar actions.
The major known effects of benzodiazepines are
anticonvulsant PA1 muscle relaxing PA1 sedative PA1 hypnotic PA1 anxiolytic PA1 antipsychotic. PA1 capability to pass the blood brain barrier in humans, PA1 a high selectivity for acetylcholinesterase as opposed to butyrylcholinesterase (about 50-fold when measured by the in vitro method by Thomsen et al., see below), PA1 a sufficient elimination half life to warrant duration of an effective concentration of at least 4 hours, probably at least 6 hours, PA1 a relatively low toxicity in therapeutical concentrations, PA1 capability of being effective in doses which are sufficiently low to keep peripheral side effects low. PA1 a) possess an at least 10-fold selectivity, preferably an at least 20-fold selectivity, more preferably an at least 40-fold selectivity, and most preferably an at least 50 fold selectivity, for acetylcholinesterase as opposed to butyrylcholinesterase, when measured by the in vitro method by Thomsen et al., see below, PA1 b) are capable of passing the blood brain barrier in humans in vivo. PA1 R.sub.3 is hydrogen, straight or branched chain alkyl of 1-6 carbon atoms, cycloalkylmethyl, phenyl, R.sub.5 -substituted phenyl, alkylphenyl, R.sub.5 -substituted alkylphenyl, heterocyclyl selected from .alpha.- or .beta.-furyl, .alpha.- or .beta.-thienyl, thenyl, pyridyl, pyrazinyl, and pyrimidyl, alkyl-heterocyclyl or R'-substituted heterocyclyl, where R' is alkyl or alkoxy, PA1 each R.sub.4 is independently selected from hydrogen, hydroxyl, sulfhydryl, alkyl, aryl, aralkyl, alkoxy, mercaptoalkyl, aryloxy, thiaryloxy, alkaryloxy, mercaptoalkaryl, nitro, amino, N-alkylamino, N-arylamino, N-alkarylamino, fluoro, chloro, bromo, iodo, and trifluoromethyl, PA1 R.sub.5 is selected from the same groups as R.sub.4, PA1 R.sub.6 is hydrogen, halo, trifluoromethyl or alkyl of 1 to 4 carbon atoms, with the proviso that when R.sup.6 is in position 7 or 9, it is preferably not halo. PA1 R.sub.8 is hydrogen or hydroxymethyl, PA1 R.sub.9 is hydrogen or alkyl of 1 to 6 carbon atoms, or when R.sub.2 is hydroxyl, R.sub.9 may be a moiety of formula II wherein R.sub.9 is hydrogen and R.sub.2 is a linking bond; or PA1 R.sub.2 and R.sub.9 may jointly form semicarbazone, PA1 X is oxygen or NR.sub.5, PA1 Y is nitrogen or phosphorus,
Thus, the benzodiazepines are relevant as drugs in connection with a broad spectrum of diseases.
The mechanism of effect of the benzodiazepine drugs are unknown, but is believed to be an effect on the GABA-system of the central nervous system. However, the effect of the benzodiazepines seems to be some kind of an overall unspecific inhibition of the central nervous system independent of the transmitter in the regions affected.
When using benzodiazepines, some of their effects are desirable, but other may be considered as side effects with respect to the specific disease treated.
When any of the anticonvulsant, the muscle relaxing, the anxiolytic or the antipsychotic effects are desired, it is often a problem that the sedative and hypnotic effects of benzodiazepines prohibit the use of high dosages of benzodiazepines, or, when such high dosages are nevertheless necessary to get a reasonable effect of the treatment, make it necessary to hospitalize the patient. Even in the dosages used, e.g. against anxiety, the sedative effect of benzodiazepines may be disadvantageous.